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Molecular Pharmacology

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Research ArticleArticle

Developmental Changes in β2-Adrenergic Receptor Signaling in Ventricular Myocytes: the Role of Gi proteins and Caveolae Microdomains

Vitalyi O. Rybin, Elena Pak, Sasha Alcott and Susan F. Steinberg
Molecular Pharmacology June 2003, 63 (6) 1338-1348; DOI: https://doi.org/10.1124/mol.63.6.1338
Vitalyi O. Rybin
Departments of Pharmacology (V.O.R., E.P., S.A., S.F.S.) and Medicine (S.F.S.), College of Physicians and Surgeons, Columbia University, New York, New York
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Elena Pak
Departments of Pharmacology (V.O.R., E.P., S.A., S.F.S.) and Medicine (S.F.S.), College of Physicians and Surgeons, Columbia University, New York, New York
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Sasha Alcott
Departments of Pharmacology (V.O.R., E.P., S.A., S.F.S.) and Medicine (S.F.S.), College of Physicians and Surgeons, Columbia University, New York, New York
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Susan F. Steinberg
Departments of Pharmacology (V.O.R., E.P., S.A., S.F.S.) and Medicine (S.F.S.), College of Physicians and Surgeons, Columbia University, New York, New York
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Abstract

Cardiomyocyte β2-adrenergic receptors (β-ARs) provide a source of inotropic support and influence the evolution of heart failure. Recent studies identify distinct mechanisms for β2-AR actions in neonatal and adult rat cardiomyocytes. This study examines whether ontogenic changes in cardiac β2-AR actions can be attributed to altered Gi expression or changes in the spatial organization of the β2-AR complex in membrane subdomains (caveolae). We show that β2-ARs increase cAMP, calcium, and contractile amplitude in a pertussis toxin (PTX)-insensitive manner in neonatal cardiomyocytes. This is not caused by lack of Gi; Gαi expression is higher in neonatal cardiomyocytes than in those of adult rats. β2-ARs provide inotropic support without detectably increasing cAMP, in adult cardiomyocytes. This cannot be attributed to dual coupling of β2-ARs to Gs and Gi, because β2-ARs do not promote cAMP accumulation in PTX-pretreated adult cardiomyocytes. Spatial segregation of β2-ARs, Gαs/Gαi, and adenylyl cyclase to distinct membrane subdomains also is not a factor, because all of these proteins copurify in caveolin-3-enriched vesicles isolated from adult cardiomyocytes. However, these studies demonstrate that enzyme-based protocols routinely used to isolate ventricular cardiomyocytes lead to proteolysis of β-ARs. The functional consequences of this limited β-AR proteolysis is uncertain, because truncated β1-ARs promote cAMP accumulation and truncated β2-ARs provide inotropic support in adult cardiomyocytes. Collectively, these studies indicate that components of the β2-AR signaling complex compartmentalize to restricted membrane subdomains in adult rat cardiomyocytes. Neither compartmentalization nor changes in Gi expression fully explain the ontogenic changes in β2-AR responsiveness in the rat ventricle.

  • Received January 22, 2003.
  • Accepted February 27, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (6)
Molecular Pharmacology
Vol. 63, Issue 6
1 Jun 2003
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Research ArticleArticle

Developmental Changes in β2-Adrenergic Receptor Signaling in Ventricular Myocytes: the Role of Gi proteins and Caveolae Microdomains

Vitalyi O. Rybin, Elena Pak, Sasha Alcott and Susan F. Steinberg
Molecular Pharmacology June 1, 2003, 63 (6) 1338-1348; DOI: https://doi.org/10.1124/mol.63.6.1338

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Research ArticleArticle

Developmental Changes in β2-Adrenergic Receptor Signaling in Ventricular Myocytes: the Role of Gi proteins and Caveolae Microdomains

Vitalyi O. Rybin, Elena Pak, Sasha Alcott and Susan F. Steinberg
Molecular Pharmacology June 1, 2003, 63 (6) 1338-1348; DOI: https://doi.org/10.1124/mol.63.6.1338
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